Title

TNF-α在高脂飼料誘發之脂肪肝老鼠造成的腎臟損傷所扮演之角色

Translated Titles

Role of TNF-α in renal damage in mice with hepatic steatosis induced by high fat diet

DOI

10.6833/CJCU.2012.00143

Authors

賴裕興

Key Words

腫瘤壞死因子α ; 脂肪肝 ; TNF-α ; hepatic steatosis

PublicationName

長榮大學醫學研究所學位論文

Volume or Term/Year and Month of Publication

2012年

Academic Degree Category

碩士

Advisor

鄭瑞棠

Content Language

繁體中文

Chinese Abstract

中文摘要 【目的】 脂肪肝(hepatic steatosis)是全球流行最廣的慢性肝病。近年來,國人在末期腎病之發生率和盛行率皆名列前茅,盛行率仍高居世界第一。本次實驗旨在研究脂肪肝動物模式對腎臟損傷之影響,並觀察TNF-α在其中所扮演的病生理角色。 【方法】 本實驗先用高脂飼料(high fat diet)來誘發C57BL/6J 公鼠(male mice) 產生脂肪肝。然後,分組用etanercept (TNF-α blockade) 或vehicle注射一個月。注射完,測量TNF-α,total cholesterol (TC), triglyceride (TG),LDL-cholesterol (LDL-C) 及HDL-cholesterol (HDL-C)。腎臟損傷由組織切片及測量血清 BUN and creatinine來觀察。並且,使用Western blot來測量C57BL/6J 公鼠的腎臟組織及培養的腎隔細胞(renal mesangial cell)中Peroxisome proliferator-activated receptors-delta (PPAR-delta)的表現。 【結果】 血清TNF-α濃度在產生脂肪肝的C57BL/6J 公鼠有顯著的升高,而etanercept改善了脂肪肝,但並未影響TC,TG, HDL-C, LDL-C 及 TNF-α濃度。etanercept顯示其腎臟保護功能因觀察到腎功能改善(recovery of serum BUN and creatinine levels)及腎組織損傷減少。腎組織PPAR-delta的表現也藉由etanercept之注射得著改善,TNF-α 對PPAR-delta 表現之影響亦在培養的腎隔細胞直接觀察到。 【結論】 本次實驗先用餵食高脂飼料誘發C57BL/6J 公鼠產生脂肪肝,發現所引起的腎臟損傷是由TNF-α上升並引發腎臟PPAR-delta 下降而產生,etanercept可以抑制TNF-α的作用,進而改善上述實驗中C57BL/6J 公鼠的腎功能及PPAR-delta之表現。

English Abstract

Abstract Aim: The present study is designed to investigate the role of TNF-α in renal damage observed in mice with hepatic steatosis. Materials and Methods: We induced hepatic steatosis in mice using high fat diet and treated mice with etanercept at the dose sufficient to block TNF-α receptors or vehicle for 1 month. Plasma TNF-α, total cholesterol (TC), triglyceride (TG), LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) were determined at the end of this treatment. Renal damage was identified by histologic observation and the higher of serum BUN and creatinine. Also, changes of PPAR-delta in kidney and renal mesangial cell (RMC) were analyzed using Western blot. Results: Serum TNF-α was markedly raised in mice showing hepatic steatosis. However, the levels of blood lipids (TC, TG, HDL-C and LDL-C) and TNF-α were not modified by the treatment of etanercept although the hepatic steatosis has been improved. Etanercept shows renal protection from histological identification and recovery of serum BUN and creatinine levels. Moreover, restoration of PPAR-delta expression by etanercept was observed in mice kidney. Direct effect of TNF-α on PPAR-delta expression was also characterized in RMC cell. Conclusion: The present study suggested that renal damage in mice with hepatic steatosis is mainly induced by increase of TNF-α through the decrease of renal PPAR-delta. Etanercept could block TNF-α to restore PPAR-delta and improve renal function in mice with hepatic steatosis.

Topic Category 醫藥衛生 > 醫藥總論
健康科學學院 > 醫學研究所
Reference
  1. 3. Fan JG, Jia JD, Li YM, Wang BY, Lu LG, Shi JP, Chan LY; Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010. Journal of Digestive Diseases 2011; 12:38-44.
    連結:
  2. 4. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003; 37: 1202-1219
    連結:
  3. 5. Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. Journal of Hepatology 2006; 45: 600-606
    連結:
  4. 6. Sanyal AJ. AGA Technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 1705-1725
    連結:
  5. 7. Lewis JR, Mohanty SR. Nonalcoholic fatty liver disease: a review and update. Digestive Diseases and Sciences 2010; 55: 560-578
    連結:
  6. 8. Tung TH, Chang TH, Chiu WH, Lin TH, Shih HC, Chang MH, Liu JH. Clinical correlation of nonalcoholic fatty liver disease in a Chinese taxi drivers population in Taiwan: Experience at a teaching hospital. BMC Research Notes. 2011; 4:315.
    連結:
  7. 9. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. American Journal of Kidney Disease 2003; 41:1-12.
    連結:
  8. 10. Kalaitzidis RG, Siamopoulos KC. The role of obesity in kidney disease: recent findings and potential mechanisms. International Urology and Nephrology 2011; 43: 771-784
    連結:
  9. 11. Yun KE, Shin CY, Yoon YS, Park HS. Elevated alanine aminotransferase levels predict mortality from cardiovascular disease and diabetes in Koreans. Atherosclerosis 2009; 205: 533-537
    連結:
  10. 12. Targher G, Kendrick J, Smits G, Chonchol M. Relationship between serum gamma-glutamyltransferase and chronic kidney disease in the United States adult population. Findings from the National Health and Nutrition Examination Survey 2001-2006. Nutrition, Metabolism, and Cardiovascular Diseases (NMCD) 2010; 20: 583-590
    連結:
  11. 13. Targher G, Bosworth C, Kendrick J, Smits G, Lippi G, Chonchol M. Relationship of serum bilirubin concentrations to kidney function and albuminuria in the United States adult population. Findings from the National Health and Nutrition Examination Survey 2001-2006. Clinical Chemistry and Laboratory Medicine (CCLM / FESCC) 2009; 47: 1055-1062
    連結:
  12. 14. Targher G, Bertolini L, Chonchol M, Rodella S, Zoppini G, Lippi G, Zenari L, Bonora E. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients. Diabetologia 2010; 53: 1341-1348
    連結:
  13. 15. Targher G, Bertolini L, Rodella S, Zoppini G, Lippi G, Day C, Muggeo M. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 2008; 51: 444-450
    連結:
  14. 16. Yilmaz Y, Alahdab YO, Ozdogan O, Dolar E. Non-alcoholic fatty liver disease and microalbuminuria in non-diabetic patients: role of insulin resistance. Internal Medicine Journal 2009; 39: 709-710
    連結:
  15. 17. Targher G, Bertolini L, Rodella S, Lippi G, Zoppini G, Chonchol M. Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis. Clinical Journal of the American Society of Nephrology (CJASN) 2010; 5: 2166-2171
    連結:
  16. 20. Wanders RJ, Waterham HR. Biochemistry of mammalian peroxisomes revisited. Annual Review of Biochemistry 2006; 75: 295–332
    連結:
  17. 21. Berger J, Gärtner J. X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects. Biochimica et Biophysica Acta. 2006; 1763: 1721-1732.
    連結:
  18. 22. Schupp M, Lazar MA. Endogenous ligands for nuclear receptors: digging deeper. The Journal of Biological Chemistry 2010; 285: 40409-40415
    連結:
  19. 23. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 1999; 20: 649-688
    連結:
  20. 24. Cowherd RM, Lyle RE, McGehee RE, Jr. Molecular regulation of adipocyte differentiation. Seminars in Cell & Developmental Biology 1999; 10: 3-10
    連結:
  21. 25. Staels B, Maes M, Zambon A. Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease. Nature Clinical Practice Cardiovascular Medicine 2008; 5: 542-553
    連結:
  22. 26. Zandbergen F, Plutzky J. PPARalpha in atherosclerosis and inflammation. Biochimica et Biophysica Acta 2007; 1771: 972-982
    連結:
  23. 27. Adkins Y, Kelley DS. Mechanisms underlying the cardioprotective effects of omega-3 polyunsaturated fatty acids. The Journal of Nutritional Biochemistry 2010; 21: 781-792
    連結:
  24. 28. Rosenson RS. Fenofibrate: treatment of hyperlipidemia and beyond. Expert Review of Cardiovascular Therapy 2008; 6: 1319-1330
    連結:
  25. 29. Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nature Reviews Immunology 2010; 10: 365-376
    連結:
  26. 30. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 2007; 447: 1116-1120
    連結:
  27. 31. Moller DE, Berger JP. Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. International journal of obesity and related metabolic disorders : Journal of the International Association for the Study of Obesity 2003; 27 Suppl 3: S17-21
    連結:
  28. 32. Yang T, Michele DE, Park J, Smart AM, Lin Z, Brosius FC, 3rd, Schnermann JB, Briggs JP. Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney. The American Journal of Physiology 1999; 277: F966-973
    連結:
  29. 33. Collino M, Benetti E, Miglio G, Castiglia S, Rosa AC, Aragno M, Thiemermann C, Fantozzi R. Peroxisome proliferator-activated receptor beta/delta agonism protects the kidney against ischemia/reperfusion injury in diabetic rats. Free Radical Biology & Medicine 2011; 50: 345-353
    連結:
  30. 34. Kolb WP, Granger GA. Lymphocyte in vitro cytotoxicity: characterization of human lymphotoxin. Proceeding of National Academy of Science of the United States of America. 1968; 61: 1250–1255.
    連結:
  31. 35. Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV. Tumor necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 1984; 312: 724– 729.
    連結:
  32. 36. Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985; 229: 869–871.
    連結:
  33. 37. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104: 487–501.
    連結:
  34. 38. Uysal S, Armutcu F, Aydogan T, Akin K, Ikizek M, Yigitoglu MR. Some inflammatory cytokine levels, iron metabolism and oxidan stress markers in subjects with nonalcoholic steatohepatitis. Clinical Biochemistry 2011; 44: 1375-1379
    連結:
  35. 39. Lee TI, Kao YH, Chen YC, Pan NH, Chen YJ. Oxidative stress and inflammation modulate peroxisome proliferator-activated receptors with regional discrepancy in diabetic heart. European Journal of Clinical Investigation 2010; 40: 692-699
    連結:
  36. 40. Karsten Peppel, David Crawford, and Bruce Beutler. A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. The Journal of Experimental Medicine 1991; 174: 1483-1489
    連結:
  37. 41. Braun J, McHugh N, Singh A, Wajdula JS, Sato R. Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly. Rheumatology (Oxford) 2007; 46: 999–1004.
    連結:
  38. 42. FDA Available: http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01240.html
    連結:
  39. 43. Pang M, de la Monte SM, Longato L, Tong M, He J, Chaudhry R, Duan K, Ouh J, Wands JR. PPARdelta agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair. Journal of Hepatology 2009; 50: 1192-1201
    連結:
  40. 44. Song HL, Lv S, Liu P. The roles of tumor necrosis factor-alpha in
    連結:
  41. structure in a mouse model of acute liver failure. BMC Gastroenterology 2009; 9: 70. doi: 10.1186/1471-230X-9-70.
    連結:
  42. 45. Hsieh TJ, Zhang SL, Filep JG, Tang SS, Ingelfinger JR, Chan JS. High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. Endocrinology 2002; 143: 2975-2985
    連結:
  43. 46. Xiong Z, Huang H, Li J, Guan Y, Wang H. Anti-inflammatory effect of PPARgamma in cultured human mesangial cells. Renal Failure. 2004; 26:497-505.
    連結:
  44. 48. Eccleston HB, Andringa KK, Betancourt AM, King AL, Mantena SK, Swain TM, Tinsley HN, Nolte RN, Nagy TR, Abrams GA, Bailey SM. Chronic exposure to a high-fat diet induces hepatic steatosis, impairs nitric oxide bioavailability, and modifies the mitochondrial proteome in mice. Antioxidants & Redox Signaling 2011; 15: 447-459
    連結:
  45. 49. Mauer SM, Steffes MW, Brown DM. The kidney in diabetes. The American Journal of Medicine 1981; 70: 603-612
    連結:
  46. 50. Pfeffer K: Biological functions of tumor necrosis factor cytokines and their receptors. Cytokine Growth Factor Reviews 2003;14: 185-191.
    連結:
  47. 51. Silva LC, Ortigosa LC, Benard G. Anti-TNF-alpha agents in the treatment of immune-mediated inflammatory diseases: mechanisms of action and pitfalls. Immunotherapy 2010; 2: 817-833
    連結:
  48. 52. Liang YJ, Jian JH, Liu YC, Juang SJ, Shyu KG, Lai LP, Wang BW, Leu JG. Advanced glycation end products-induced apoptosis attenuated by PPARdelta activation and epigallocatechin gallate through NF-kappaB pathway in human embryonic kidney cells and human mesangial cells. Diabetes/Metabolism Research and Reviews 2010; 26: 406-416
    連結:
  49. 53. Reyes-Martin P, Alique M, Parra T, Hornedo JP, Lucio-Cazana J. Cyclooxygenase-independent inhibition of H2O2-induced cell death by S-ketoprofen in renal cells. Pharmacological Research (The Official Journal of the Italian Pharmacological Society) 2007; 55: 295-302
    連結:
  50. 54. Neeraja Kambham, Glen S Markowitz, Anthony M Valeri, Julie Lin and Vivette D D'Agati Obesity-related glomerulopathy: an emerging epidemic. Kidney International 2001; 59:1498–1509
    連結:
  51. 55. Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiology and Drug Safety 2011; 20:119-130.
    連結:
  52. 56. Nishanthi Thalayasingam, John D. Isaacs. Anti-TNF therapy. Best Practice & Research Clinical Rheumatology 2011; 25: 549–567
    連結:
  53. References
  54. 1. USRD 2009 ADR/reference tables. Available: http://www.usrds.org/2011/view/v2_12.asp
  55. 2. NKF KDOQI GUIDELINES Available: http://www.kidney.org/professionals/KDOQI/guidelines_ckd/
  56. 18. Machado MV, Goncalves S, Carepa F, Coutinho J, Costa A, Cortez-Pinto H. Impaired renal function in morbid obese patients with nonalcoholic fatty liver disease. Liver International : Official Journal of the International Association for the Study of the Liver 2012; 32: 241-248
  57. 19. Gabaldón T . Peroxisome diversity and evolution. Philosophical Transactions of the Royal Society of London. Series B, Biologicl Sciences 2010; 365: 765–773
  58. colon tight junction protein expression and intestinal mucosa
  59. 47. Zu N, Li P, Li N, Choy P, Gong Y. Mechanism of saikosaponin-d in the regulation of rat mesangial cell proliferation and synthesis of extracellular matrix proteins. Biochemistry and Cell Biology.2007 85:169-74.